Westernization of diet has resulted in an increase of patients suffering from lifestyle-related diseases such as hyperlipidemia, diabetes, and hypertension. Some of these diseases finally lead to arteriosclerotic diseases such as myocardial infarction, angina pectoris, and cerebral infarction. It is important to reduce risk factors such as hyperlipidemia, diabetes, hypertension and smoking habit as much as possible in order to prevent arteriosclerotic diseases or improve the quality of life. As a result of a main epidemiological study made on the incidence of hyperlipidemia and coronary artery diseases, the serum total cholesterol (hereinafter abbreviated as “T-Cho”) concentration or the serum triglyceride (hereinafter abbreviated as “TG”) concentration shows a positive correlation with the onset of the coronary artery diseases. In particular, the serum low-density lipoprotein cholesterol (hereinafter abbreviated as “LDL-Cho”) concentration shows a much stronger positive correlation therewith. On the other hand, the serum high-density lipoprotein cholesterol (hereinafter abbreviated as “HDL-Cho”) concentration shows a negative correlation therewith.
Omega-3 polyunsaturated fatty acids (hereinafter abbreviated as “ω3PUFAs”) including α-linolenic acid, icosapentaenoic acid (hereinafter referred to as “EPA”), and docosahexaenoic acid (hereinafter referred to as “DHA”) are known. Omega-3PUFAs and their pharmaceutically acceptable salts and esters (hereinafter referred to as “ω3PUFA salts/esters”) exhibit various actions including anti-arteriosclerotic action, platelet aggregation inhibitory action, hypolipidemic action, anti-inflammatory action, antitumor action and central action, and are therefore incorporated in various food products or commercially available as health food products or pharmaceutical products.
A high purity EPA ethyl ester (hereinafter referred to as “EPA-E”) is commercially available in Japan in the trade names of Epadel and Epadel S (manufactured by Mochida Pharmaceutical Co., Ltd.) as drugs for alleviating ulcers, pain and chill associated with arteriosclerosis obliterans and for treating hyperlipidemia. Soft capsules containing about 46 wt % of EPA-E and about 38 wt % of DNA ethyl ester (hereinafter referred to as “DHA-E”) are commercially available in the U.S., Europe, and other countries in the trade names of Omacor and Lovaza as therapeutic agents for hypertriglyceridemia.
A statin compound (hereinafter also referred to as statin) is a generic name used to refer to a drug for lowering cholesterol levels in blood by inhibiting the action of HMG-CoA reductase. The result that the onset of coronary artery diseases was suppressed by the use of statin compounds in the therapy for hyperlipidemia is obtained in a large-scale clinical trial.
Six statins are currently available in Japan as pharmaceutical products. Based on the physicochemical properties (log P7.4; water-octanol partition coefficient at a pH of 7.4), these statins are classified into two groups including water-soluble statins (pravastatin (−0.84), rosuvastatin (˜0.33)) and fat-soluble statins (atorvastatin (1.11), simvastatin (1.60) and the like). (Non-Patent Literature 1) Pravastatin sodium, rosuvastatin calcium and atorvastatin calcium which are the corresponding pharmaceutical products have partition coefficients (octanol-water partition coefficient) of −0.33 (Non-Patent Literature 2), −0.3±0.1 (Non-Patent Literature 3) and 1.21 (Non-Patent Literature 4), respectively.
In recent years, a single pharmaceutical preparation (compound preparation) containing a plurality of pharmaceutically active ingredients is under active development in the pharmaceutical field in order to improve, for example, the pharmacodynamic synergism, the reduction of side effects, the convenience for patients and the compliance.
A large-scale randomized controlled clinical trial PELTS trial) was conducted to know the effect of Epadel on the suppression of the onset of ischemic heart diseases in patients administered with a statin for the treatment of hyperlipidemia, and its main analysis shows the evidence that the incidence of major coronary events is significantly low in the group administered with Epadel in combination according to the comparison between the administered group and the non-administered group. (Non-Patent Literature 5) When attention is focused on the treatment of lifestyle-related diseases, it is deemed significant for the medication to take notice of the clinical effects of the ω3PUFAs and the statins and to develop compound preparations containing both the drugs.
Various reports have been made on preparations (compound preparations) each containing two pharmaceutically active ingredients in which an ω3PUFA alkyl ester and a statin which are liquid at room temperature are encapsulated. However, several problems are to be solved to supply stable preparations over the manufacture, distribution and storage periods, and these preparations are not yet in practical use.
Statin compounds such as pravastatin sodium and atorvastatin calcium hydrate are HMG-CoA reductase inhibitors and are used as excellent oral drugs for treating hyperlipidemia or hypercholesterolemia. However, it is already known that such statin compounds have a 7-substituted-3,5-dihydroxy-6-heptenoic acid structure and are unstable with respect to high temperature, high humidity and light because of the molecular structure and are excessively destabilized due to the intramolecular lactonization, isomerization, oxidation, decomposition or the like in the acidic region and that stable preparations cannot be obtained unless at least the pH is more than 7. Preparation using alkaline excipients at a pH of more than 9 such as calcium carbonate, anhydrous disodium phosphate, sodium hydroxide, potassium hydroxide and magnesium oxide (Patent Literatures 1, 2, 3) and preparation using magnesium metasilicate aluminate at a pH of more than 9 as the stabilizer (Patent Literatures 4, 5, 6) have been reported in order to solve this problem. However, there is no application to soft capsules or to drugs combined with ω3PUFA salts/esters and the applicability is uncertain.
The main ingredient of gelatin widely used in capsules is protein. Protein is known to have the property of being easily modified by the application of physical factors (e.g., heating, freezing, vigorous agitation) and chemical factors (e.g., addition of acids, bases, organic chemicals and heavy metal ions), thus losing the water solubility to be insolubilized. In fact, when gelatin is used in the capsule coating, it is known that the solubility of the coating generally tends to be reduced over time by crosslinking caused by the interaction of gelatin molecules with an encapsulated material or the material after decomposition. That is, the gelatin capsule coating may be modified depending on the formulation condition and there is concern that the function as the pharmaceutical composition may be lost.
A soft gelatin capsule obtained by suspending a microcapsule comprising at least one polymer and a statin in an ω3PUFA alkyl ester has been reported. (Patent Literature 7) Even when the manufacturing process is performed at a temperature of 40° C., the statin can be prevented from being decomposed by incorporating the statin in the microcapsule upon compounding of the statin in a pharmaceutically active liquid ingredient containing the ω3PUFA alkyl ester in a large amount. However, the amount of statin to be incorporated is limited because the stability during the distribution and storage after the manufacture is uncertain, the microcapsule amount is 1 to 60% of the total amount of the preparation and the statin content in the microcapsule is 1 to 40% of the total amount of the microcapsule. In addition, this technique is only applied to fat-soluble statins and it is not certain whether it can be applied to water-soluble statins.
A capsule prepared by combining at least one ω3PUFA salt/ester, at least one statin, and optionally at least one hydrophilic solvent and/or at least one surfactant and/or other solubilizer and/or other excipient has been reported (Patent Literature 8). However, it would be difficult to control the content of the statin ingredient within a predetermined allowable range during the manufacture because the stability of the capsule is not mentioned and is hence uncertain, there is concern about side effects due to a high surfactant content and the statin is not completely dissolved in the ω3PUFA. In addition, this technique is only applied to fat-soluble statins and it is not certain whether it can be applied to water-soluble statins.
A pharmaceutical composition comprising a hard or soft capsule containing a ω3PUFA salt/ester as a first active pharmaceutical ingredient, a carrier and optionally a solubilizer and a coating of a statin serving as a second active pharmaceutical ingredient formed on the hard or soft capsule has been reported (Patent Literature 9). However, the pharmaceutical composition will have difficulty in controlling the content of the statin ingredient within a predetermined allowable range and suffer from a complicated step and a low yield when the coating is formed,
A seamless capsule comprising an ω3PUFA alkyl ester encapsulated in the form of a liquid pharmaceutical composition, wherein (1) a statin serving as a solid pharmaceutically active ingredient is dispersed in a capsule shell layer, (2) the statin is dispersed in the liquid pharmaceutical composition or (3) the statin is applied onto the capsule shell layer having no pharmaceutically active ingredient has been reported (Patent Literature 10). However, since the stability is not mentioned and is uncertain in the shapes of (1) and (3) and the solid ingredient is present in the capsule coating in the shape of (1), there is concern about the stability of the seamless capsule and it is deemed to be difficult to increase the amount of the solid pharmaceutically active ingredient; and in the shapes of (2) and (3), the pharmaceutical composition will have difficulty in controlling the content of the statin ingredient as described above within a predetermined allowable range and suffer from a low yield. In addition, this technique is only applied to fat-soluble statins and it is not certain whether it can be applied to water-soluble statins.